Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle - Insight from analysis of a transgenic mouse model

To examine the role of muscle AMP-activated protein kinase (AMPK) in maximal exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle, we generated muscle-specific transgenic mice carrying cDNAs of inactive AMPK alpha 2 (alpha 2i TG). Fed blood glucose was slightly higher in alpha 2i TG mice compared to wild type littermates, however, the difference was not statistically significant. In alpha 2i TG mice, glucose tolerance was slightly impaired in male, but not in female mice, compared to wild type littermates. Maximal exercise capacity was dramatically reduced in alpha 2i TG mice, suggesting that AMPK alpha 2 has a critical role in skeletal muscle during exercise. We confirmed that known insulin-independent stimuli of glucose transport including mitochondrial respiration inhibition, hyperosmolarity, and muscle contraction increased both ANIPK alpha 1 and alpha 2 activities in isolated EDL muscle in wild type mice. While, alpha 2 activation was severely blunted and a I activation was only slightly reduced in alpha 2i TG mice by these insulin independent stimuli compared to wild type mice. Mitochondrial respiration inhibition-induced glucose transport was fully inhibited in isolated EDL muscles in alpha 2i TG mice. However, contraction- or hyperosmolarity-induced glucose transport was nearly normal. These results suggest that AMPK alpha 2 activation is essential for some, but not all insulinindependent glucose transport. (c) 2007 Elsevier Ireland Ltd. All rights reserved.